FDA Briefing Document
Blood Products Advisory Committee
Meeting
January 9, 2009
Atryn® [antithrombin III
(recombinant)]
GTC Biopharmaceuticals Inc.
Division of Hematology
OBRR/CBER/FDA
TABLE OF
CONTENTS
PAGE
1.0 GENERAL
INFORMATION
3
PRODUCT NAME
PRODUCT COMPOSITION
PROPOSED INDICATION
DOSING REGIMEN AND
ROUTE OF ADMINISTRATION
SYNOPSIS OF MANUFACTURING PROCESS
2.0 EXECUTIVE
SUMMARY
7
3.0
INTRODUCTION AND BACKGROUND
9
4.0
REGU
5.0 BASIS FOR
LICENSURE 12
6.0 CLINICAL
OVERVIEW
12
6.1
PHARMACOKINETIC STUDIES
12
6.2 EFFICACY
AND SAFETY STUDIES
13
6.3 RESULTS OF
PHASE 2 AND PHASE 3 EFFICACY AND SAFETY
STUDIES
15
7.0
CONCLUSIONS
22
8.0 QUESTIONS
TO THE COMMITTEE
23
APPENDIX 1
VIRAL INACTIVATION/REMOVAL
24
APPENDIX 2
DOSE ADMINISTRATION AND
DOSE MONITORING
FOR PHASE 2 STUDY GTC AT III
01002
25
APPENDIX 3
DOSE ADMINISTRATION AND
DOSE MONITORING
FOR PHASE 3 STUDY GTC AT III 012-04
27
APPENDIX 4
ADVERSE EVENTS
29
1.0 GENERAL
INFORMATION
PRODUCT NAME
ESTABLISHED NAME:
Antithrombin III
(recombinant)
PROPOSED TRADE NAME:
ATryn®
PRODUCT COMPOSITION (from the
Applicant’s proposed label):
ATryn®, Antithrombin III
(Recombinant), for Injection is a nanofiltered, sterile, terminally heat-treated
lyophilized dosage form. It is a 432 amino acid glycoprotein with a molecular
weight of approximately 57,215
Recombinant antithrombin III (rATIII) is produced by recombinant DNA technology using genetically engineered goats into which the gene for human antithrombin has been introduced along with a mammary gland specific promoter, which directs expression of the protein in the milk. The goats in which rATIII is produced are USDA certified scrapie-free, and specific pathogen-free.
Using a reference standard calibrated against a World Health Organization international standard for antithrombin III concentrate, each vial of ATryn contains 1,750 international units (IU) of antithrombin III (250 mg of rATIII). The product is formulated with citrate, chloride, and glycine, and each vial contains 100 mg glycine, 79 mg sodium chloride, and 26 mg sodium citrate. When reconstituted with 10 mL Sterile Water for Injection, the pH is 7.0. Following reconstitution, the solution may be further diluted into 0.9% sodium chloride for injection.
ATryn does not contain antimicrobial preservatives nor is it formulated with human plasma proteins. rATIII is affinity purified using a heparin resin. ATryn is a purified product, and contains less than 0.0002 IU heparin per IU rATIII.
The purification and drug product manufacturing process have been validated to ensure removal and/or inactivation of viruses and prions. The purification and drug product manufacturing process, which include both nanofiltration and heat treatment steps, have been challenged with a panel of viruses of different types and have shown capable of minimally achieving ≥8 to ≥25.3 log10 reductions. The goats are from a closed, USDA certified scrapie-free herd. The purification process was further challenged to remove prions. The process was shown capable of achieving a ≥ 11.3 log10 reduction.
Manufacturer:
GTC
Biopharmaceuticals Inc.
PROPOSED INDICATION: ATryn is
indicated for the prevention of peri-operative and peri-partum thromboembolic
events in hereditary antithrombin deficient patients.
DOSING REGIMEN:
The
dosage of ATryn is individualized for each patient.
The goal
of treatment with ATryn is to restore and maintain functional antithrombin
activity levels between 80 -120% (0.8 – 1.2 IU/mL) of normal to prevent
thromboembolic
events during peri-opertive and peri-partum period
Initial treatment includes a loading dose of ATryn targeting an antithrombin activity level of 100%. The initial loading dose is based on the patient’s pre-treatment functional AT activity level and body weight in kilograms.
Dosing
Formula for (non pregnant) Patients
The loading dose:
Dose (IU) = [(100 - pre-treatment AT activity
level in %) /2.28] x Body Weight in kg
The loading dose should be given as a 15 minute infusion followed immediately by initiation of the maintenance infusion.
The maintenance dose is administered by continuous infusion. The maintenance dose, expressed in IU/hour, is determined using the following formula:
Dose (IU/hour) = [(100 - pre-treatment AT
activity level in %) /10.22] x Body Weight in kg
The
usual maintenance dose is 4-5 IU/kg/h.
Dosing
for Pregnant Women
The loading dose is determined using the following formula:
Dose (IU) = [(100 - pre-treatment
antithrombin activity in %) / 1.25] x Body Weight in kg
The
loading dose should be given as a 15 minute infusion followed immediately by
initiation of the maintenance infusion.
The
maintenance
dose is
administered by continuous infusion. The maintenance dose, expressed in IU/hour,
is determined using the following formula:
Dose (IU/hour) = [(100 - pre-treatment
antithrombin activity in %) / 5.43] x Body Weight in kg.
ROUTE OF
ADMINISTRATION:
Intravenous
POTENCY: Each vial is labeled with the nominal potency of no less than 1750 IU/vial (250 mg/vial). Each vial contains the following excipients: 104.8 mg Glycine, 82.8 mg sodium chloride, 27.1 mg sodium citrate. ATryn is reconstituted with 10 mL of Sterile Water for Injection.
SYNOPSIS OF THE
MANUFACTURING PROCESS:
The active ingredient in ATryn is a recombinant form of human ATIII that is produced in the milk of transgenic goats. Fine details of the manufacturing process are not provided in this briefing document due to their proprietary nature.
Herd of transgenic
goats and collection of milk (source material)
The transgenic goat was obtained after microinjection of the DNA expression construct (transgene) in the pro-nucleus of a goat embryo. The transgene is composed of the cDNA of human ATIII and the regulatory elements (promoter) of the goat beta casein gene. The latter drives the expression of ATIII in the goat mammary gland. The selection of the first transgenic goat F0 (male founder) was based on the transgene status (DNA sequence integrity and germline transmission) and its capability to express rATIII in high quantity in the milk (induced by prolactin).
Goat breeding is accomplished through a combination of natural breeding and artificial insemination. To secure continuation of the manufacture, a --(b)(4)------ transgenic animal banking system has been established, -----------------------(b)(4)------------------------------------------------------(b)(4)------comprised of qualified male and female goats, and the semen from qualified male goats. The genetic stability of the transgene has been demonstrated up to seven generations of goats. Qualification of goats to the production herd is based on genotyping, assessment of milk composition and content of rATIII, microbiological and adventitious agent screening of the milk pools, and examination of animal health. Source material (milk) is collected from qualified does, frozen, and shipped to ------(b)(4)--------------------------- (contract manufacturer for BDS) facility for further processing.
In order to optimize the consistency of the source material, which shows certain variability with regards to the amount of milk components and characteristic of ATIII molecule, a milk pooling strategy has been incorporated. Compositional analysis of batches demonstrated that acceptable level of consistency has been achieved.
Purification of
ATryn bulk drug substance (BDS)
Purification begins with thawing, pooling and clarification of the source material, followed by filtration steps, three chromatography columns, and filtration though a virus retention nano-filter. The BDS is formulated before for the final production steps.
The viral filtration step was added in 2006 and did not negatively affect product safety and efficacy as demonstrated in clinical trials.
Analysis of data from three consecutive batches of BDS and their in-process controls was performed to support the consistency of the manufacture process.
Removal of milk-derived impurities by the purification process was adequately validated by analyses of milk production pools and BDS batches derived from the validation studies or designated for the commercial distribution. Suitably validated analytical assays were used to demonstrate the efficient removal of these impurities.
Characterization
of structure and function
The structure of rATIII is consistent with published data on plasma-derived ATIII (pdATIII) with N-terminal variability in the first two or three amino acids (£ 10% of the product) but larger truncations have not been detected. Four methionine residues have been identified as potential oxidation sites.
Recombinant ATIII and pdATIII are glycosylated with each containing 3-4 N-linked carbohydrate moieties. However, they differ in monosaccharide composition and oligosaccharide structure. These differences account for the increased affinity (about fourfold) of rATIII to heparin compared to pd-ATIII. The functional in vitro assays for ATIII activity are not affected since they are performed in the presence of excess heparin.
BDS
specifications
Specifications and validation of analytical methodology provided for the control of BDS are deemed acceptable. Each batch of BDS is tested for identity, purity, and potency. The specifications are justified by results from conformance batches, nonclinical and clinical studies. All routine methods used as control or release test of starting materials, process intermediates, drug substance, drug product, and stability samples were validated as appropriate.
Milk contaminants are known allergens and may be present in trace amounts in the product. Therefore, they are monitored with a variety of assays. A Warning and Precaution statement will be included in the product label to preclude patients with hypersensitivity to goat proteins or goat milk components.
Manufacture of
Final Drug Product (FDP)
The final product is manufactured by -------------------(b)(4)-------------------------------, The --------(b)(4)---------Netherlands where the product is aseptically filled, lyophilized, and subjected to a terminal sterility and viral inactivation step by heat treatment. Viral clearance data for various manufacturing steps of ATryn® are summarized in Appendix 1.
The analytical control of the finished product is similar to that performed on the BDS. The in vitro assay of product potency is based -----------------------------(b)(4)----------------------------------------------(b)(4)--------------------------------. The assay is consistent with the assay routinely used to measure the potency of plasma-derived (pd) ATIII. The internal reference standard was calibrated against the WHO IS ATIII concentrate and the potency of ATryn is expressed in IU.
Control of
Adventitious Agents
Viral safety and control of scrapie agents are adequately addressed. The pathogen safety of ATryn relies on the control of goats, starting material (milk), and documented clearance of pathogens by the manufacturing process.
The goat herd is closed and comprises of selected animals
with limited origins (
Stability of ATryn
Final Drug Product
Stability studies were performed on three (3) lots of ATryn stored at 2oC - 8oC. Results of the studies support the shelf life of the product of 30 months.
Based upon in-use stability studies, the reconstituted product should be administered within 8 hours of preparation.
2.0 EXECUTIVE
SUMMARY
This briefing document contains a summary of FDA’s
evaluation of efficacy and safety data provided by GTC Biotherapeutics Inc.
to support
approval of ATryn® indicated for the prevention
of peri-operative
and peri-partum thromboembolic events in hereditary antithrombin deficient
patients.
The
dosage of ATryn® is individualized for each patient. The goal of treatment with
ATryn is to restore and maintain functional antithrombin activity levels between
80 -120% (0.8 – 1.2 IU/mL) of normal to prevent thromboembolic events.
The proposed release
specification potency is (b)(4) IU/vial, with
a shelf-life of 2 years when stored at 2°C–25°C (36°F-77°F).
The Biologics Licensing
Application (B
- GTC AT III 01002: Phase 2 study to assess the incidence of thromboembolic events following prophylactic intravenous (iv) administration of antithrombin (rhAT) to hereditary antithrombin (AT) deficient patients in high-risk situations compared to the historical control (see below)
- GTC AT HD 012-04: Phase 3 study multicenter, multinational study to
assess the safety
- GTC AT HD-R 013-04: Historical
cohort study to assess the incidence of
thromboembolic events following
prophylactic intravenous administration of plasma derived antithrombin to
hereditary antithrombin (AT) deficient patients in high-risk
situations.
- AT III-009-00: A comparative single-dose Pharmacokinetic
study of rhAT III with
Plasma derived ATIII in hereditary
antithrombin (AT) deficient patients
Efficacy
Efficacy was evaluated in studies GTC AT III 01002
Immunogenicity
Immunogenicity to ATryn™ was assessed by measuring serum
antibodies against ATIII, plasma derived ATIII, goat ATIII
Safety
The safety profile of ATryn
™ when used for prevention
of peri-operative and peri-partum thromboembolic events in hereditary
antithrombin deficient patients at the
recommended dose schedule is acceptable. Bleeding (intra-abdominal hemorrhage in a
pregnant female and hemarthrosis in a surgical patient) was reported in two subjects. Concomitant
administration of heparin may enhance the pharmacodynamic action of ATryn. Both
the patients recovered without sequelae. There were no deaths and no adverse
events that led to study discontinuation.
Safety with repeat exposure
will be evaluated in a post marketing study.
Conclusions
ATryn at the recommended dose
is effective in reducing prevention
of peri-operative and peri-partum thromboembolic events in hereditary
antithrombin deficient patients. The safety profile appears to be
acceptable. The immunogenicity on
repeat exposure remains to be evaluated.
3.0
INTRODUCTION AND BACKGROUND
Antithrombin (ATIII) is a 58 kDa single chain glycoprotein that contains 423 amino acids and has a carbohydrate content of about 15%. The protein has 3 disulfide bridges and 4 N-linked glycosylation sites (Asn 96, 135, 155, and 192).
ATIII is a serine protease inhibitor that is the principal inhibitor of the blood coagulation serine proteases thrombin (Factor IIa) and Factor Xa, and to a lesser extent, Factors IXa, XIa, XIIa, trypsin, plasmin, and kallikrein. ATIII neutralizes the activity of thrombin and other serine proteases by forming an irreversible 1:1 stoichiometric complex between enzyme and inhibitor. In the presence of heparin, the normally slow formation of complex becomes dramatically accelerated. The ability of ATIII to inhibit thrombin can be enhanced by more than 1000 fold when ATIII is bound to heparin. The thrombin-antithrombin complex (TAT) is rapidly removed by binding to a receptor in the liver. The half-life of TAT complex is less than 5 minutes in humans. ATIII is also referred to as heparin cofactor. Localization of a fraction of the ATIII on the endothelial surface, where enzymes of intrinsic coagulation cascade are commonly generated, enables ATIII to rapidly neutralize these activated clotting factors and protect natural surfaces against thrombus formation.
The mean concentration of ATIII in human plasma is about 0.1 g/L. The biological activity of 1mL of pooled human plasma in a thrombin or FXa inhibition assay is defined as 1 IU/mL. Normal ranges for the assay are between 80% and 120%.
Hemophilia (2008)14, 1229-1239
Congenital ATIII deficiency (Hemophilia 2008, 14, 1229-1239: Patnaik and Moll)
Antithrombin (AT) deficiency was first described in 1965 by Olav Egeberg in a family in which several family members had venous thromboembolism (VTE). Egeberg also established the deficiency to be an autosomal dominant disorder. Most cases are heterozygous. Homozygosity for AT deficiency is always fatal in utero. Inherited AT deficiency is uncommon with prevalence rates for AT deficiency of 1 in 2000- 5000 in the overall population. The types of AT deficiency are shown in the table below:
Patients with
congenital deficiency present with thromboembolic events (TE). TE in hereditary AT deficient
patients are uncommon prior to puberty but increase thereafter, particularly
during periods of high risk, such as pregnancy, surgery, or bed rest. Hereditary
AT deficiency causes a life-long increased risk of venous thromboembolism
and
up to 70% of cases
do develop a venous thromboembolic event (VTE) during their lives
Often VTEs are
recurrent and may be life-threatening. The risk of development of VTEs as
compared to the normal population in these situations is increased by a factor
of 10 to 50. Failure to properly treat hereditary AT deficient patients,
especially during high risk situations such as surgery or trauma or for pregnant
women, during the peri-partum period, may result in VTE. Asymptomatic hereditary
AT deficient patients generally do not require anticoagulant prophylaxis, except
in settings of increased risk. Hereditary AT deficient
individuals with a history of one thrombosis are treated with chronic oral anticoagulant
prophylaxis.
4.0 REGU
There
is currently one plasma derived Antithrombin III product licensed in the
The
following summarizes the regulatory chronology of this
BLA:
March 2001 Pre-IND Meeting with sponsor to discuss clinical development of the product for prevention of thrombosis in hereditary AT deficient patients
December 2002 Second pre-IND meeting for the above indication
March 2003
August 2003
August 2003
November 2003 Clinical Hold removed
April 2004 GTC requests a pre-BLA meeting. CBER advises that a second study will be needed to support licensure. CBER also advises GTC to develop a sensitive assay for evaluation of immunogenicity.
July 2004 Phase 3 protocol submitted.
November 2005 Phase 3 study initiated
August 2006 Approved by EU for prevention of peri-operative thromboembolism in hereditary deficient patients
October 2007 Pre-BLA meeting
November 2007 Orpahn drug designated
December 2007 Fast track designation granted.
January 2008 Rolling BLA submitted
August 2008 Clinical module of the BLA submitted and PDUFA timeline initiated
August 2008 Priority review granted
February 2009 Regulatory action due date
5.0 BASIS FOR
LICENSURE
The applicant conducted Phase 2 and 3 historically controlled studies to
evaluate prevention of peri-operative
and peri-partum thromboembolic events in hereditary antithrombin deficient
patients. A total of 31 patients were enrolled in the ATryn arm and 35 matched
controls were selected from patient records obtained from 20 international
sites.
In
addition, the applicant conducted a population pharmacokinetic analysis
of Atryn and compared it to human plasma-derived antithrombin in 15 congenital deficient patients
6.0
CLINICAL
OVERVIEW
6.1 PHARMACOKINETIC STUDIES:
AT III-009-00:
Randomized Pharmacokinetics of AT III in Patients with hereditary AT III
deficiency receiving two doses 50 and 100 IU/kg:
This was an open-label, single dose pharmacokinetic study in male and female patients (≥ 18 years of age) with hereditary AT III deficiency. The patients received either 50 (n = 9 all females) or 100 (n = 6, 2 males and 4 females) IU/kg ATryn intravenously. Blood samples were collected before the administration of the drug and at 5, 10, 15, 30, 45, and 60 minutes and at 2, 4, 6, 8, 24, 48, and 72 hours. The clearance and half-life of ATryn were 9.6 and 7.2 mL/hr/kg and 11.6 and 17.7 hours following 50 and 100 IU/kg dose, respectively. The incremental recovery was 2.07 ± 1.54 %/IU/kg body weight.
AT III-009-00: Population pharmacokinetic
analysis of recombinant human antithrombin and comparison to human
plasma-derived antithrombin:
The objective of this investigation was to compare the pharmacokinetics of ATryn and plasma-derived antithrombin (pdAT) using population-pharmacokinetic approach.
The pharmacokinetics of ATryn
were evaluated in 15 patients with congenital antithrombin deficiency following
a short intravenous infusion of 50 or 100 IU/kg. The pharmacokinetics of pdAT were
evaluated from a study performed in 1984 in the
|
Parameters |
rhAT |
pdAT |
|
CL (mL/hr/kg) |
9.5 |
1.3 |
|
Half-life (hrs) |
10.2 |
91.2 |
|
Vss (liters) |
7.7 |
9.8 |
Conclusions: Plasma-derived AT has almost a 9-fold longer half-life and 7-fold slower clearance than ATryn.
6.2 EFFICACY AND
SAFETY STUDIES
GTC AT III 01002: “Phase 2 study to assess the incidence
of thromboembolic events following prophylactic intravenous (iv) administration
of antithrombin (rhAT) to hereditary antithrombin (AT) deficient patients in
high-risk situations.”
This was a single arm, multicenter, multinational,
open-label study with blinded evaluation of the ultrasonographic images. 15 hereditary AT deficient patients
(documented AT activity ≤ 60% of normal and with previous history of
thromboembolism) scheduled for surgery, Caesarean section, or vaginal delivery
qualified for the study were
treated prophylactically with ATryn. Dosing with ATryn was individualized to
increase and maintain target AT activity levels between 80% and 120% of normal.
Functional AT activity levels were used to monitor and adjust dosing.
ATryn administration to patients scheduled for surgery and
patients scheduled for
Caesarean section or delivery was initiated approximately
24 hours before the planned
procedure and continued for a minimum of 3 days. ATryn
therapy was continued, until effective chronic anticoagulation therapy was
established and the patient was mobilized and ready for hospital discharge (See
APPENDIX 2).
In pregnant patients not scheduled for Caesarean section or
induction of delivery,
treatment was initiated only when the patient was
hospitalized and in active labor.
Treatment of these patients was also continued for a
minimum of 3 days and continued until effective chronic anticoagulation therapy
was established and the patient was mobilized and ready for hospital
discharge.
A blinded, independent determination of the incidence of
acute DVT based on duplex
ultrasound examination was the primary measurement of the outcome of treatment
with ATryn. Standardized duplex ultrasound examination of the lower extremities
was used to establish the presence or absence of acute DVT. Duplex ultrasound
studies were performed and interpreted by qualified specialists within
the same hospital/institution on a real time basis for the timely and
appropriate clinical care of the patient. Venography could be used, when
clinically indicated, if the study investigator felt that duplex ultrasound
results were inconclusive. For other TE relevant diagnostic modalities were
used.
GTC AT HD 012-04: “Phase 3 study multicenter, multinational
study to assess the safety
The trial design for this study
was similar to the phase 2 study.
This was a single arm, open-label
multi-center, multinational study in 18 patients. Congenital AT deficient
patients scheduled for surgical procedures (with personal histories of TE and documented AT levels less than
60%) and pregnant patients were enrolled in the study.
Dosing with ATryn was to be individualized to increase and
maintain target AT activity levels between 80% and 120% of normal. Functional AT
activity levels were used to monitor and adjust dosing. For elective
procedures (i.e. non-pregnant surgery patients and pregnant patients
scheduled for Caesarean
section or delivery induction), treatment with ATryn was initiated up
to 24 hours prior to
the scheduled procedure. For pregnant patients not scheduled for
Caesarean section or
delivery induction, treatment with ATryn was started as soon as they
were admitted to the
hospital and active labor had begun. The dosing algorithm was revised for
pregnant patients based on phase 2 results (See APPENDIX
3).
Administration of
ATryn was continued for a minimum of 3 days for all study patients
and
continued until effective chronic anticoagulation therapy
was established and the patient was mobilized and ready
for hospital discharge. The
protocol-specified maximum duration
of treatment was
limited to 14 days.
The incidence of
thromboembolic events was assessed clinically in all patients who were treated
with ATryn. Signs and symptoms indicative of the occurrence of a thromboembolic
event were monitored during treatment with ATryn and up to and including 7 days
after cessation of ATryn treatment. If signs and symptoms indicated the
occurrence of a thromboembolic event appropriate diagnostic tests were
performed to confirm or exclude the presence of the event.
GTC AT HD-R 013-04: Historical
cohort study to assess the incidence of
thromboembolic events following
prophylactic intravenous administration of plasma-derived antithrombin to
hereditary antithrombin (AT) deficient patients in high-risk situations. Both
studies (GTC ATIII 01002
This was an international, multi-center, prospectively
designed retrospective cohort study of hereditary AT deficient patients who had
a history of thromboembolic events, an elective procedure performed since 1
January 1997 that placed them at high risk for the occurrence of a
thromboembolic event, and at that time, were treated prophylactically with
intravenous administration of plasma-derived AT for a minimum of 2 days.
Approximately 5 to15 sites were planned for participation
in the study. All
eligible study sites had a listing or automated medical
record system that identified patients
who had hereditary AT deficiency
and/or those patients who had received plasma
AT during high-risk elective procedures since 1 January
1997.
All the patients identified were selected. A minimum of 35
up to a maximum of 70 patients identified from the listing or automated medical
record system of all patients eligible patients at the sites were included in
the study. The eligibility criteria were the same as for the study conducted
with ATryn. Clinical outcomes
in terms of TE were noted in the case report form.
Statistical Methods for Determining the Efficacy
End-Point
The statistical approach used was to establish non-inferiority by comparing the incidence of any TE event with plasma-derived ATII vs. ATryn (results were combined from Phase 2 and 3 studies). The non inferiority margin was set at 20%. Use of a one-sided lower confidence bound, instead of a confidence interval, consistent with use of a one-sided test for a non-inferiority study was adopted. The 95% confidence interval based on the exact (Clopper-Pearson) method for the proportion of patients with presence of DVT for both groups was presented.
Safety Monitoring
In both studies the patients were evaluated for laboratory parameters of coagulation (INR, aPTT, and anti-Xa activity) and immunogenicity (up to 90 days after treatment). Active assessment of any bleeding complications was performed and included a brief physical examination, hemoglobin and hematocrit measurements, and urinalysis every day during ATryn administration through the last day treatment. In addition, blood serum samples were collected to allow for retrospective infectious or immunological evaluations in the future, if indicated.
6.3 RESULTS OF
PHASE 2 AND PHASE 3 EFFICACY AND SAFETY STUDIES
Study Objectives and Endpoints
The objective of the two studies was to assess the incidence of thromboembolic events following prophylactic IV administration
of ATryn in situations
associated with a high risk for thromboembolic events and to evaluate the safety of ATryn in patients with
hereditary AT deficiency.
The primary endpoint of the two
studies (combined) was non-inferiority of incidence of TE during and within
seven days of treatment with ATryn compared with a historical cohort control of
comparable patients treated with plasma derived ATIII.
Results of the Phase 2 AT III 01002 study:
FDA analysis consists of intent to treat population defined by all patients who received at least one dose of ATryn. Of the 14 patients enrolled, one patient had baseline a DVT but had received treatment with ATryn as diagnosis of baseline DVT was made after the patient had been treated. However this patient is excluded in the efficacy analysis for prevention of thrombosis. Of the 13 patients 5 were treated peri-operatively and 8 were treated during the peri-partum period. All 13 patients had a prior history of TE. Patients’ ages ranged from 21 to 74 years with a mean of 36.7 years. The mean baseline AT activity level for surgical patients was 50% and the median was 53% and for pregnant patients the mean AT levels were 46% and the median was 45%.
All 13 patients were
observed for clinical signs and symptoms of thromboembolic events. One patient had lower leg edema and venous distension for several days during Atryn
treatment and another patient had venous distention before, during and following
the dosing period. Both the patients were negative for acute DVT by ultrasound
examination.
All patients were evaluated for acute DVT by duplex
ultrasonography examinations, which were interpreted both locally as well as
under blinded conditions centrally by an independent imaging laboratory. Acute
DVT was identified by both the central and local readers for one surgery patient
during treatment, i.e. a treatment failure. This patient received ATryn for a total
of nineteen days
Diagnostic imaging was performed in three patients to
exclude the presence of
suspected thromboembolic events [to rule out pulmonary
embolism (PE)
thromboembolic event.
Administration of ATryn according to the protocol-defined dosing and monitoring scheme
resulted in adequate control of AT activity levels within the desired 80 to 120% range in
four of the five surgical patients. Four of the 5 surgery patients received an average of 2.5 (range 1-8) bolus ATryn administrations during the course of their treatment period (see table below).
AT activity levels
dropped below the lower limit of normal for all 5 surgery patients when rhAT
administration was discontinued. Central laboratory AT activity levels at 30,
60,
For the 8 delivery patients, administration of ATryn according to the protocol defined
dosing and monitoring scheme resulted in adequate control of AT activity levels within
the desired 80 to 120% range. Bolus dosing increased AT activity levels to within or above the normal range with the exception of 3 of the 8 delivery patients who required between 12-15 dose adjustments to keep the levels between 80-120% as specified in the dosing regimen schedule. Because of the numerous dose adjustments needed in one third of the pregnant patients, FDA advised the sponsor to revise the dosing algorithm for these patients in the phase 3 study (see below)
ATryn treatment duration, rhAT dose administration and dose adjustments
|
Group/Patient Number |
Treatment Duration (days) |
Total loading doses (IU/kg) |
Dose per day (IU/kg/day) |
Dose adjustments |
|
Surgery group ---(b)(6)---- ---(b)(6)---- ---(b)(6)---- ---(b)(6)---- ---(b)(6)---- |
12 8 13 19 10 |
50.0 47.1 38.2 35.1 21.0 |
166.0 157.1 79.5 179.9 113.7 |
3 4 4 8 1 |
|
Pregnant Group ---(b)(6)---- ---(b)(6)---- ---(b)(6)---- ---(b)(6)---- ---(b)(6)---- ---(b)(6)---- ---(b)(6)---- ---(b)(6)---- ---(b)(6)---- |
10 3 3 3 4 4 5 3 3 |
48.6 21.0 26.9 27.2 19.7 23.7 81.4 25.3 20.3 |
293.0 222.0 331.6 207.0 249.5 286.5 451.7 167.0 277.4 |
12 2 4 14 2 2 6 1 15 |
IU= international units
In conclusion, one out of thirteen patients developed a DVT
and was considered a treatment failure. This study was not considered for
licensure because there was no comparator for efficacy and the safety data
especially with regards to thrombogenicity were insufficient.
Results of
the Phase 3
GTC AT HD 012-04 study:
A total of 23 patients were
enrolled in the study with 18 (78.3%) of the 23 patients receiving treatment
with ATryn. All 18 (100.0%) ITT population patients completed the study. The reasons
for five of the enrolled patients who were not included as ITT population
of the study were: (i) ineligible due to DVT at baseline, (ii) went
into
spontaneous labor, (iii) spontaneous amniorrhexis, (iv) fetal Doppler results
were pathological hence withdrew consent
In the safety and
the ITT population, six of the ATryn-treated patients were non-pregnant surgery
patients and 12 were pregnant patients. The Per Protocol population was
comprised of 6 non-pregnant surgery patients and 11 pregnant patients.
One patient was not included in the
Per Protocol population because the patient’s treatment started after delivery,
instead of before delivery as specified in the protocol.
The mean patient age was 37.2
years (21-62 years). The mean screening AT activity level was 50.9% and ranged from 29.0% to 65.7%
with Although some screening AT activity levels were above 60%, patients met all the inclusion criteria, and had
historical levels confirming hereditary AT deficiency.
Concomitant medications for all
patients included the heparin group of anticoagulants.
For the primary efficacy
endpoint, the Intent-to-Treat Population
(ITT) was defined as those patients who
received ATryn and had at least one follow-up assessment after initiation of
treatment with ATryn. The ITT population included 6 non-pregnant surgery
patients and 12 pregnant patients.
The Per Protocol
Population included those
patients who received ATryn
The Per Protocol
population included 6 non-pregnant surgery patients and 11
pregnant
patients.
Safety Population: This population
included all patients who received at least 1 dose of
ATryn. The Safety
population included 6 non-pregnant surgery patients and 12
pregnant
patients.
The efficacy of
ATryn for the prophylaxis of thromboembolic events in
surgical
During treatment
and during the follow-up period of 7 days after cessation of treatment with
ATryn, no thromboembolic events occurred in the intent to treat population (n =
18). The patients included in this study all had significant prior personal
histories of venous thromboembolic events which elevated the risk for recurrence
of such events in this study.
On the basis of
the efficacy results, it is concluded that ATryn is effective in preventing
potentially life-threatening thromboembolic events in patients with congenital
deficiency during the peri-operative or peri-partum
period.
There were 2
venous thromboembolisms reported in the study after the 7-day post-treatment
follow-up period. A DVT was reported 11 days after discontinuation
of
treatment with
ATryn
In conclusion, the data from the
current study demonstrates the efficacy of ATryn for the prevention of
thromboembolic events in congenital deficient patients in high risk situations
Treatment duration and dose
administration and dose adjustments
|
Group |
Treatment Duration (days) |
Total loading doses (IU/kg) |
Dose per day (IU/kg/day) |
Dose adjustments |
|
Surgery group N=6 Mean Median Range |
7 3 3-14 |
21.6 19.2 13.5-34.4 |
37.8 21.2 15-78.5 |
2.5 2.0 1-6.0 |
|
Pregnant Group N=12 Mean Median Range |
4.4 3.6 1-14.0 |
36.3 35.5 13.0-57.6 |
38.9 30.2 7.2-139.9 |
1.5 1.0 0.0-6.0 |
Please note with the revised
dosing algorithm for pregnant patients, the number of dose adjustments needed
was significantly reduced compared to the Phase 2 Study.
Conclusion of Overall
Efficacy:
Patients for the control group
(pdATIII) were matched, as for as possible, for demographics, medical/surgical
history, history of prior TEs, surgical procedure, baseline AT activity
levels
|
|
Test (31) |
Control (35) |
|
TE Outcome |
|
|
|
Positive |
1 |
0 |
|
Negative |
30 |
35 |
|
|
P-value |
95% Confidence Interval (P2-P1) | ||
|
Type |
1-sided |
2*1-sided |
Lower Limit |
Upper limit |
|
Asymptotic |
0.1422 |
0.2843 |
-0.1634 |
0.0698 |
|
Exact |
0.2401 |
0.4802 |
-0.167 |
0.0778 |
The
primary efficacy endpoint is the incidence of any thromboembolic event after the
start of treatment (pdAT or rhAT) and within 7 days following discontinuation of
treatment. Clopper Pearson exact 95% confidence interval for the proportion of
patients with a thromboembolic event is presented for each treatment group, as
well as the exact 95% lower confidence bound for the difference between
treatments. Non-inferiority
is
demonstrated as the lower 95% confidence bound of the difference is
≥-0.20.
Safety:
During dosing, five (83.3%) of
the six surgery patients
Table showing AEs
that were severe in intensity
|
Patient |
Type of
AE |
Relationship
to ATryn |
|
Surgery |
Severe
headache |
Not
related |
|
Pregnant |
Dilutional anemia with no evidence
of bleeding.
Muscle
spasm |
Not
related Not
related |
|
Pregnant |
Enterobacter
sepsis |
Not
related |
|
Pregnant |
Vaginal
tear |
Not
related |
TEAE occurring in two or more
patients treated with ATryn due to all causes are presented
below:
|
Body System/ preferred
term |
TEAE incidence
|
Number of
events |
|
Total number of patients
|
18
(88.9) |
63 |
|
Anemia |
3
(16.7) |
3
(4.8) |
|
Vaginal
laceration |
3
(16.7) |
3
(4.8) |
|
Non cardiac chest pain
|
2
(11.1) |
2
(3.2) |
|
Edema
peripheral |
2
(11.1) |
2
(3.2) |
|
Urinary tract
infection |
2
(11.1) |
2
(3.2) |
|
Post procedural
hemorrhage |
2
(11.1) |
2
(3.2) |
|
Headache |
2
(11.1) |
5
(7.9) |
|
Syncope |
2
(11.1) |
2
(3.2) |
|
Hematoma |
2
(11.1) |
2
(3.2) |
Immunogenicity:
No patients
developed anti ATIII antibodies. Data on repeat exposure to the product is very
limited and is being evaluated in post marketing studies.
7.0
CONCLUSIONS
ATryn has been shown to
be efficacious, using the recommended dosing guidelines, for prevention of
peri-operative and peri-partum thromboembolic events in hereditary antithrombin
deficient patients. Careful monitoring of AT activity levels during treatment is
recommended. The safety profile appears to be acceptable.
8.0 QUESTIONS
TO THE COMMITTEE
Q1
Do the data show safety
a) Is the safety profile acceptable?
b) Is rATIII effective in preventing TE in non-pregnant surgical subjects and in pregnant subjects during the peri-partum period?
Q2
Should post-marketing studies be performed to assess safety and immunogenicity after repeat dosing?
APPENDIX 1
APPENDIX
2
DOSE ADMINISTRATION
AND DOSE MONITORING FOR PHASE 2 STUDY GTC AT III 01002
For a patient with a pretreatment baseline AT activity of X%, the dose required to increase
and maintain the AT activity level at 100% will be as follows:
Loading Dose (IU) =
((100 – X)/2.28) x Patient Weight
(Loading dose in international units equals 100 minus ‘X’ divided by 2.28, then multiplied
by patient weight (in kg), where ‘X’ is the patient’s pre-dose AT activity level.)
The loading dose should be given as a 15 minutes infusion immediately followed by the
maintenance dosing. For easier programming of the infusion pump, the calculated bolus dose can be multiplied by 4 (four) to obtain the IU/h to be given for a period of 15 minutes.
Maintenance Dose
(IU/day) = ((100 – X)/0.426) x Patient Weight
(Maintenance dose in international units per day equals 100 minus ‘X’ divided by 0.426,
then multiplied by patient weight (in kg), where ‘X’ is the patient’s pre-dose AT activity
level.)
Therapeutic monitoring and Dose Adjustment:
After the start of the maintenance dose infusion, blood for AT activity levels should be
drawn at 0.5 hour (i.e. this is 45 minutes after the start of the loading dose infusion). Based
on the result of this AT activity level, the infusion rate (and consequently the dose) should be adjusted using the following guideline:
1. If
the AT activity level is between 80%
Take an AT activity level 4 hours calculated from the time of the previous AT activity blood draw.
2. If the AT activity level is less than 80%, increase the maintenance infusion rate by
50% and take a blood AT activity level 0.5 hour after the infusion rate adjustment.
3. If the AT activity level is greater than 120%, decrease the infusion rate by 30% and
take a blood AT activity level 0.5 hour after the infusion rate adjustment.
When the next AT activity level is available, based on these results the dose will be adjusted again using the following guideline:
1.
If the AT activity level is between 80%
In case this is the second consecutive AT activity level that is within the target
range, next blood sample should be taken at least every 24 hours afterwards
(calculated from the start of treatment) for the duration of treatment with rh AT.
In case this is the first AT activity level that is within the target range, take an AT
activity level 4 hours calculated from the time of the previous AT activity blood
draw.
2. If the AT activity level is less than 80%, increase the maintenance infusion rate by
50% and take a blood AT activity level 0.5 hour after the infusion rate adjustment.
3. If the AT activity level is greater than 120%, decrease the infusion rate by 30% and
take a blood AT activity level 0.5 hour after the infusion rate adjustment.
This cycle of AT activity checking will be repeated until there are two consecutive samples that show an activity in the target range of >80% and <120%, and at least every 24 hours afterwards (calculated from the start of treatment) for the duration of treatment with rh AT.
It is possible that the procedure or delivery will influence AT activity levels. Therefore, an additional check of the AT activity level should be done approximately one hour after the surgery or delivery. In case the activity level is below 80% a 15 minutes bolus infusion of AT can be given to quickly restore the AT activity level. The dose can be calculated with the formula:
Bolus Dose (IU) =
((100 – Y)/2.28) x Patient Weight
(Bolus dose in international units equals 100 minus ‘Y’ divided by 2.28, then multiplied by patient weight (in kg), where ‘Y’ is the patient’s post-surgery or delivery AT activity level.)
For easier programming of the infusion pump, the calculated bolus dose can be multiplied by 4 (four) to obtain the IU/h to be given for a period of 15 minutes. In order to check the effect of this, an AT activity level blood sample is recommended 0.5 hour after the bolus dose administration was stopped.
All
administrations of rh AT will be carefully documented in the patient’s CRF.
APPENDIX
3
DOSE
ADMINISTRATION AND DOSE MONITORING FOR PHASE 3 STUDY GTC AT HD
012-04
Dosing for
Non-pregnant Surgical Patients
For
non-pregnant surgical patients the required loading dose is determined using the
following formula:
Loading Dose (IU) =
[(100 – patient’s pre-treatment antithrombin activity in %) divided by 2.28] x
Patient Weight in kg
For
example, a loading dose in a non-pregnant surgical patient with a baseline AT
activity of 50% would be approximately 22 IU/kg bodyweight. The loading dose
should be given as a 15 minute infusion immediately followed by initiation of
the maintenance infusion.
For
easier programming of the infusion pump, the calculated loading dose can be
multiplied by 4 to obtain the IU/hour to be given over a period of 15
minutes.
The
required maintenance dose for non-pregnant surgical patients is given as a
continuous
infusion
and is determined using the following formula:
Maintenance Dose
(IU/hour) = [(100 – patient’s pre-treatment antithrombin activity in %) divided
by10.22] x Patient Weight in kg
For
example, a maintenance dose in a non-pregnant surgical patient with a baseline
AT activity of 50% is approximately 5 IU/kg/h. See the AT activity monitoring
and dose adjustment recommendations
Dosing for Pregnant
Patients
For
pregnant patients the required loading dose is determined using the following
formula:
Loading Dose (IU) =
[(100 – patient’s pre-treatment antithrombin activity in %) divided by 1.25] x
Patient Weight in kg
For
example, a loading dose in a pregnant patient with a baseline AT activity of 50%
is
approximately
41.5 IU/kg bodyweight. The loading dose should be given as a 15 minute infusion
immediately followed by initiation of the maintenance infusion. For easier
programming of the infusion pump, the calculated bolus dose can be multiplied by
4 to obtain the IU/hour to be given over a period of 15
minutes.
The
required maintenance dose for pregnant patients is given as a continuous
infusion and is determined using the following formula:
Maintenance Dose
(IU/hour) = [(100 – patient’s pre-treatment antithrombin activity in %) divided
by 5.43] x Patient Weight in kg
For
example, a maintenance dose in a pregnant patient with a baseline AT activity of
50% is approximately 9 IU/kg/h. The patient weight used for both the loading
Therapeutic
AT activity Monitoring
surgical
and pregnant patients)
The
maintenance dose should be adjusted on the basis of laboratory measurements
of
antithrombin
activity. Response to rhAT may vary in individual patients, achieving different
levels of in vivo recovery and different half-lives. Frequent antithrombin
activity assessments and dosing adjustments may be necessary when starting
treatment and just after surgery or delivery.
Antithrombin
activity should be checked 2 hours after initiation of the loading dose. In case
the antithrombin activity is below 80% or above 120%, the maintenance infusion
rate should be increased or decreased by 30%, respectively.
Two
hours after a dose adjustment or if no adjustment was made, approximately 6
hours after the start of infusion, another antithrombin activity sample should
be taken. Again, in case the antithrombin activity is below 80% or above 120%,
the maintenance infusion rate should be increased or decreased by 30%,
respectively.
Subsequently,
antithrombin activity should be checked 1-2 times a day and dose adjustments
made accordingly. The antithrombin activity should be maintained above 80% for
the duration of the treatment.
All
administrations of rhAT and any dose adjustments should be carefully documented
in the patient’s CRF.
APPENDIX
4
List of Serious TEAE
|
System
Organ Class | |||||
|
Protocol/
Patient Number |
Preferred
Term |
Reported
Term |
Severity |
Relation |
Outcome |
|
Gastrointestinal
Disorders | |||||
|
|
Intra-abdominal
Hemorrhage |
Intra-abdominal
Bleeding |
Severe |
Definite/
Probable |
Recovered |
|
General
Disorders and Administration site
Conditions | |||||
|
|
Pyrexia |
Fever
Unknown Origin |
Moderate |
Not
Related |
Recovered |
|
Injury,
Poisoning and Procedural Complications | |||||
|
|
Femur
Fracture |
Traumatic
Fracture of Left Femur |
Severe |
Remote/
Unlikely |
Recovered |
|
Infections
and Infestations | |||||
|
|
Enterobacter
Sepsis |
Septicemia
Enterobacter Cloacae |
Severe |
Not
Related |
Recovered |
|
Investigations | |||||
|
|
Hemoglobin
Decreased |
Low
Hemoglobin Level |
Moderate |
Possible |
Recovered |
|
Musculoskeletal
and Connective Tissue disorders | |||||
|
|
Hemarthrosis |
Clinical
Hemarthrosis R Knee |
Moderate |
Not
Related |
Recovered |
|
Nervous
System Disorders | |||||
|
|
Grand
Mal Convulsions |
Grand
Mal Seizures |
Severe |
Remote/
Unlikely |
Recovered |
|
Respiratory,
Thoracic and Mediastinal Disorders | |||||
|
|
Pulmonary
Embolism |
Bilateral
Pulmonary Embolism |
Severe |
Not
Related |
Recovered
with Sequelae |
|
Vascular
Disorders | |||||
|
|
Hypotension |
Hypotension |
Moderate |
Remote/
Unlikely |
Recovered |
|
|
Wound
Hemorrhage |
Wound
Hemorrhage |
Moderate |
Remote/
Unlikely |
Recovered |
|
|
Deep
Vein Thrombosis |
Muscular
Vein Thrombosis Left Upper Leg |
Mild |
Remote/
Unlikely |
Recovered |
|
|
Deep
Vein Thrombosis |
Popliteal
Non-occlusive Thrombus in RLE |
Moderate |
Not
Related |
Recovered |
|
|
Hematoma
|
Hematoma |
Moderate |
Remote/
Unlikely |
Recovered |